β-Amino acids are of interest in the preparation of active pharmaceutical ingredients (APIs). The β-amino acid moiety in APIs of interest is normally part of a complex whole structure. Complexity is typically enhanced when considering a chiral center at the β-position of the β-aminobutyryl group and the general desire to obtain enantiopure compounds.
A particularly interesting class of APIs having β-amino acid structural moieties are dipeptidyl peptidase-4 (DPP-4) inhibitors which act as antidiabetic agents. DPP-4 inhibitors are oral antidiabetic drugs which reduce glucose blood levels by a new mechanism of action in which the DPP-4 inhibitors (“gliptins”) inhibit inactivation of glucagon-like peptide (GLP), which stimulate insulin secretion. The benefit of these medicines lies in their lower side-effects (e.g., less hypoglycemia, less weight gain) and in the control of blood glucose values. It can be used for treatment of diabetes mellitus type 2.
The first member of the novel pharmacological group is sitagliptin which is chemically (R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one and which has the following structural formula
including a β-amino acid part.
However, an inclusion of a β-amino acid framework into a more complex molecule remains a permanent challenge for industrial production.
This is well reflected in the literature for the synthesis of sitagliptin. Several methods are described how to introduce the β-amino acid structure into the molecule of sitagliptin. The first synthesis of sitagliptin molecule disclosed in WO 03/004498 uses an unusual chiral dihydropyrazine promoter, diazomethane and silver salts, which compounds are unacceptable reagents for industrial synthesis. The synthetic pathway of WO 03/004498 is depicted in Scheme 1.

Since then, several trials to improve this unacceptable method have been published in literature. In general, regarding the structure of sitagliptin, which is composed from the β-amino acid part and the heterocyclic part, synthetic routes can be divided in two approaches.
In the first general approach, a heterocycle is coupled to the system in earlier steps of the synthesis, while the desired configuration of β-amino acid part is constructed later. This approach seems less feasible, because typically, it is better to couple more complicated and more expensive parts of molecule in last steps. A typical example of this approach is shown in Scheme 2.

There is no good method for non-chromatographical chiral resolution of final compound 1 (WO 09/084024), so the resolution is performed by enantioselective reduction of 15 to 1. Such enantioselective hydrogenation of β-enamino acid derivatives requires expensive precious metal catalysts, such as rhodium (WO 03/004498, Tetrahedron Asymmetry 17, 205 (2006)) or ruthenium (WO 09/064476) and expensive ligands, such as ferrocenyl diphosphine ligands—JOSIPHOS catalysts (WO 04/085378, WO 05/097733, WO 06/081151, WO 11/113399, J. Am. Chem. Soc., 126, 9918 (2004)), while the compound 15 is less suitable for routine chiral enzymatic approaches due to bulky unnatural derivatisation of carboxylic part.
Another option is a derivatization of the amino group with a chiral group. Chiral resolution is then achieved by hydrogenation with a cheaper achiral catalyst, by crystallisation of diastereomeric mixtures or by combination of both methods, as depicted in Scheme 3 (WO 04/085661, WO 09/085990, WO 11/025932, WO 11/060213, WO 11/142825). These methods suffer from considerable loss of material in order to obtain pharmaceutical grade chiral purity.

In the second general approach, a heterocycle is coupled to the β-amino acid in later steps. The corresponding δ-aryl-β-amino acids are readily available from the corresponding β-keto acids, prepared from acetic acids and malonic derivatives (WO 09/064476, WO 10/122578, WO 10/131025, WO 11/127794). Unfortunately, the amino group needs protection before coupling with the heterocycle in order to eliminate side reactions. As can be gathered from Scheme 4, the protection/deprotection scenario considerably prolongs the synthesis of antidiabetic agents (Scheme 4).

There are several methods in literature how to prepare enantiomerically enriched or pure intermediates 18, 19, 20, and 21, such as by enantioselective reduction of 17 (WO 09/064476), by introducing chiral protecting groups with further diastereoselective crystallization (CN 102126976), by crystallization of diastereomeric salt of compounds (±)-18, (±)-19, (±)-20, or (±)-21 with chiral acids (WO 10/122578, WO 10/131025, J. Chem. Res. 2010 (4), 230), or by introduction of a chiral center via natural source, such as aspartic acid derivatives (WO 11/035725, WO 11/116686A2, CN 102093245, CN 10212697) or by enzymatic approach.
Yet another option is creating a chiral center by selective reduction of β-keto acid derivatives. Precious metal catalysts (WO 04/087650, Org. Prep. Res. & Dev. 9, 634-639 (2005)) or enzymatic reduction (WO 09/045507) can be used, while the transformation of the obtained chiral hydroxyl intermediates to final sitagliptin precursors via azetidinone intermediates is laborious, as can be gathered from Scheme 5.

A hypothetical shortening of this conversion could be realized by preparation of an N-unsubstituted azetidinone having the structural formula

However, the synthesis is very complicated and is realized by introduction of toxic hydroxylamine. In a characteristic literature example, only the non-fluoro analogue of the aforementioned N-unsubstituted azetidinone is prepared, while 2,4,5-fluoro analogues were prepared according to the reaction pathway depicted in Scheme 4, that is not via azetidinone derivatives (Org. Biomol. Chem., 8, 893 (2009)). Furthermore, an opening of the four-member ring of the N-unsubstituted azetidinone with nitrogen nucleophiles is accomplished by a complex reaction mixture with carbonic acid derivatives such as tert-butyl dicarbonate or chloroformates (WO 04/089362, WO 08/019124, Bioorg. Med. Chem. Lett. 13, 241 (2003, Tetrahedron Lett. 43, 3951 (2002), Org. Biomol. Chem, 1, 2670 (2003), ES 2335380).
Therefore, there is still a need for a simplification of industrial synthesis of β-amino acid derivatives as intermediates in the synthesis of dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin.